The long-term goal of this proposal is to identify novel gene mutations underlying essential tremor (ET) to gain insights into its biology and etiology, which are poorly understood. ET is one of the most common neurological diseases in adult life whose prevalence increasing steadily with age. The main motor symptom of ET is an 8- to 12-Hz postural or kinetic tremor of the arms; however, the vast majority of ET patients also develop other motor and non-motor manifestations, frequently causing misdiagnosis. Since most people with ET benefit, or partially benefit, from drug therapy, prompt diagnosis and appropriate treatment are necessary for delaying or preventing the functional disabilities that often make ET patients face financial and other difficulties. In the last few years, exome sequencing (ES) has proved its ability to identify causal alleles for inherited diseases, even in families previously deemed statistically underpowered for positional cloning, and is becoming a fruitful strategy for gene identification in both Mendelian and more complex traits. In this context, because conventional cloning techniques have failed to identify causal genes for ET, we strongly believe that exome sequencing is the most appropriate technique for accelerating gene discovery in essential tremor. Therefore, based on our previous works and own preliminary data that disease genes can readily be identified through the use of ES, the goal of the proposed project is to identify novel gene mutations underlying tremor by applying ES in a clinically and ethnically homogeneous group of patients with ET. The use of genetically homogenous families will reduce both locus and allelic heterogeneity, thus increasing statistical power for gene discovery. To carry out this proposal, we have collected DNA samples from over 100 ET patients, including eight large families, eleven small families, as well as sporadic patients. All proposed ET patients are from the same geographical region in the North of Spain and are subject to an ongoing full clinical trial that includes exhaustive clinical, neurophysiological, neuroimaging, and neuropsychological examinations. All patients developed disease symptoms before the age of 40, suggesting that genetic factors are likely to play a major role in disease development. Based on our preliminary data, we anticipate that novel gene mutations underlying ET will be identified upon completion of the proposed project, thus facilitating the understanding of tremor's overall etiology, prognosis, and treatment. In addition, we strongly believe that the identification of novl tremor genes will greatly contribute to the comprehension of other neurodegenerative diseases such as Parkinson's disease, as having ET increases the risk for developing Parkinson's disease. Lastly, since gene discovery leads directly to model systems, better understanding of pathogenesis, improved diagnostic tests, and novel targets for drug development, the proposed project will enormously contribute to the translation of basic biomedical research into clinical practice, thus benefiting human health and reducing health care cost.